Method of manufacturing the individual racemates of n-(p-hydroxyphenylisopropyl) arterenol and products



United States Patent It is known from Dutch patent specification No. 86,359 that a compound according to Formula I a b no-onon-onz-Nn-oncm-om --on I HO has properties which are particularly interesting in pharmacological respect, so that this substance may be used in medicine notably as a bronchospasmolyticum. As is well-known, the said compound is preferably manufactured by reducing a ketone of Formula II to the alcohol of Formula I.

However, a particular disadvantage of the product thus obtained results from the fact that two asymmetrical centres, indicated by a and b in Formula I, are present in the molecule. When starting in the usual -way from the racemic ketone of Formula II, the asymmetrical centre a is introduced during reduction, so that the resulting product consists of a mixture of two pairs of optical an-tipodes. If the possible configurations of the centres a and b are indicated by '1 or d and l or d respectively, the four stereoisomers l'd, l'l, d'd and d'l occur. When starting from the racemic ketone, the sums of the compounds having configurations l'd and 1'1 and those having configurations d'd and dl are then equal, it is true, but the two ture of racemates is always obtained the free base of which has a melting point of about 167 C., but this melting takes place with dissociation so that it must not.

be concluded therefrom that the composition of the mixture is constant. Thus, also if the mixture of racemates obtained by reduction of the ketone of Formula I is desired to be used as such, it is necessary first to manufacture the individual racemates and test the properties thereof, in order to be able to determine the composition of the remelting mixture with the aid of any differences found in the properties of the-two pure racemates. As a matter of fact in such a test of the pure racemates, their pharmacological properties will also be examined thoroughly, not only to determine if one of the two racemates may have substantially the bronchospas-molytiic activity known for the mixture, but also to iind out how addition-a1 actions and any further actions present in the mixture in eventually masked form are divided over the two components of the mixture.

However, it has been found very diflicult to separate the mixture of racemates of Formula I into the pure racemic components. None of the methods known for separating such a mixture of racemates yields the desired result. The mixture of racemic bases could be obtained in crystalline form only by the crystallization from water described in the aforementioned Dutch patent specification. It appeared impossible to isolate fractions of different properties by fractional crystallizations. Another point is that such catecholamines are very oxidab-le so that dissociation readily occurs during prolonged crystallizations. Also salts of bases according to Formula I were found to be crystallizable very diiiicultly and unsuitable for separating the mixture of racemates by fractional crystallization.

According to the present invention, this problem which is specific for the manufacture of racemically pure compounds of Formula I, may be solved by first manufacturing-in known manner a mixture of racemates of the tribenzyl ether of Fonrnula III CHz-O difierent racemates ll-l-d'd and dl-l-l' d may all the same be present in diiferent amounts. As regards the stereospecificity of the reduction of the ketone according to Formula II it can only be predicted that certainly not only one of the two possible racemates will be formed, but on the other hand it may not be taken for certain that the two racemates necessarily occur in equal amounts, in other words, that stereospecificity may not occur at all in this reaction. Even if stereospecificity would not occur at all in this reaction, a mixture of racemates of variable composition could otherwise still be obtained, for example due to difference in solubility of the two racemates. For the use of a therapeutically active substance in medicine it is very important to have the security that the substance to be administered is always the same. For the manufacture of the bronchospasmolyticum of Formula I this means that either the mixture of racemates is separated into its two components, or use is made of a manufacturing method in which the two race-mates are always obtained in the same mixing ratio. Now, in conventional manufacturing methods, thesituation is such that amix- It was found that pure racemates could be obtained from a mixture of racemates of the said new compound by fractional crystallization either of the free bases, or of salts of the mixture. The racemically pure compounds of Formula I are obtained by subsequently splitting off the benzyl groups from the racemically pure tribenzyl ethers by a methodknown per se for this type of reactions, for example by catalytic hydrogenation.

In conformity therewith the present invention relates to a method of manufacturing racemically pure compounds of Formula I or salts thereof and is characterised in that a mixture of racemates of Formula III or of salts thereof is manufactured by methods known per se and the racemically pure compounds are isolated from this mixture by fractional crystallization, these racemically pure tribenzyl ethers subsequently being converted into the pure racemic compounds of Formula I or salts thereof by hydrolysis or hydrogenation.

The mixture of racemates of the tribenzyl ether according to Formula III is preferably manufactured by reduction of the corresponding ketone of Formula IV which ketone may be obtained, for example, by condensation of the wbromine ketone of Formula V with the amine of Formula VI The reduction of the tribenzyl keto'ne to the corresponding alcohol must naturally be effected so that the benzyl groups are not also replaced by hydrogen atoms. A catalytic hydrogenation cannot therefore be used in this case. The ketone is preferably reduced to the alcohol with the aid of a metal hydride, such as LiAlI-L, or NaBI-I or a dialkylaluminiurn hydride, such as diisobutylaluminium hydride or diisopropyla-luminium hydride. Very satisfactory results are obtained, for example if the reduction of the ketone is effected with the aid of NaBI-I, in water,

or in a lower aliphatic alcohol, for example methanol or ethanol or in mixtures of these alcohols and water.

According to the invention, the resulting racemic mixture of free bases or salts thereof is crystallized by fractionating. Alternatively, various fractions of the mixture of free bases may first be crystallized and then converted into salts, whereaf-ter the various salt fractions are purified further by fractional crystallization.

Suitable solvents for the crystallizations are aromatic or aliphatic hydrocarbons, for example benzene, toluene or petroleum ether, ethers, for example diethyl ether, diisopropyl ether, tetrahydrofurane or dioxane, lower aliphatic alcohols, for example methanol, ethanol, propanol or butanol, ltetones, for example acetone, methyl-ethyl ketone or methylisohutyl ketone or mixtures of these solvents.

Thus, for example, from the crystalline mixture of bases as obtained, in substantially theoretical yield, by reduction of the ketone with a melting range of about55 to 75 (1., two fractions were crystallized by fractional crystallization from ether, one having a melting range from 69 to 76 C., hereinafter referred to as the tribenzyl-a base, and one traction melting at 92.5 to 94.5 C., referred to as the rtribenzyl-B base. The two fractions could be converted, by treatment with benzoic acid, into sharply-mew ing benzoic-acid salts: the tribenzyl-a-benzoate with melting point from 156 to 158 C. and the tribenzyl-p-benzoate with melting point from 138.5 to 139 C.

A characteristic of the 'tIibCHZYI-oc base is that it may occur in two modifications of difierent melting points. In

fact, it has been found, that, if the base melting at about 72 C. was converted to the corresponding benzoate with melting point from 156 to 158 C. and if this base was then isolated again :by adding lye to an aqueous solution of this salt, now a base with a melting point of 72 C., and now one with a melting point of 88 C. was obtained, without it being possible to indicate what circumstances are determinative of the formation'of one modification or the other. The fact that the same pure base in two dififerent modifications is concerned may be concluded from the (following .points:

(a) A base with the one melting point as well as one with the other melting point could be obtained from the same sharply-melting base via the benzoate.

(b) Mixing the base of the lower melting point with a small amount of the base of the higher melting point caused a rise in melting point of the mixture to about 85 C.

Either base provides, in quantitive yield, the sharply-melting benzoate with melting point from 156 to 158 C.

(d) U-pon heating above the melting point (about 80 C.) the base of the lower melting point resolidi-fied. The resulting product melted at 84.5 to 89 C.

From both the pure tribenzyl-ix base and the tribenzyl-fi base, a plurality of pharmacologically acceptable acid addition crystalline salts could be obtained such as, for example: the p-nitrobenzoate with melting points from 133 to 134 C. and from 126 to 127 C., respectively; the nicotinate with melting points from 129 to 130 C. and from to 136 C., respectively; themalein-ate with melting points from 122 to 124 C. and from 137.5 to 138 C., respectively; the hydrochloride with melting points from 98 to 99 C. and from 95 to 97 C., respectively.

Thus, such salts of the pure racemic bases may also be isolated from the racernic mixture of bases obtained upon reduction of the tribenzyl ketone, by first converting this mixture of bases into a mixture of salts and then separating the mixture of salts by fractionated crystallization.

More particularly a conversion of the mixture of bases into the p-toluene sulphonate was foundto give very satisfactory results. In fact, this salt of the tribenzyl-a compound crystallizes very d-iflicult-ly, whereas that of the tribenzyl-p compound is readily obtained in crystalline form. For example the mixture of bases is dissolved in a mixture of from 50% to 95% of ethanol and from 50% to 5% of water, then an equivalent amount of p-toluene sulphonic acid is added thereto a r/hereafter the solution is inoculated with crystals of the p-toluene sulphonic acid salt of the tribenzyl-fi-racemate. It has been found that only the salt of the tribenzyl-B base then crystallizes in pure form with a melting point from 137 to 138.5" C. From this salt, the pure tribenzyl-fi "base with melting point from 94 to 95 C. is obtained by hydrolysis.

The residue of the base is separated from the filtrate of the crystallized salt by adding caustic-soda lye and from this the pure tribenzyl-fi-racernate may be formed after recrystallization.

Of the resulting pure racemates of Formula III or of salts thereof, the benzyi groups may be replaced, by methods known per se by hydrogen atoms for obtaining the racemically pure compounds of Formula I.

The compounds of Formula III are preferably converted into those of Formula II by hydrogenation in the presence of Raney nickel or a catalyst of rare metal. The compound of Formula I is obtained in good yield in a simple manner, more particularly by hydrogenation of a salt of the compound according to Formula III, for example of the benzoic-acid salt, with the aid of a palladium catalyst.

The differences in melting points (dissociation points) of both the salts and the free bases of the pure racemates of Formula I thus, obtained were found to be particularly small. Also the dissociation points of the racemically pure bases differ but slightly from that of the mixture of racemic bases manufactured in accordance with Dutch patent specification No. 86,359.

The two benzoates show clear differences in crystal form, that of the a-base crystallizing from water into rosettes which do not weather in drying after having been dried over P 0 in vacuo at 60 C. and the benzoate of the ,G-base crystallizing from water into thin plates containing about 11% of crystal Water. This B-benzoate is hygroscopic after drying over P 0 Ina provisional pharmacological test it could be ascertained that the fl-raceniate had a bronchospasmolytic activity about thrice that of the u-racemate.

EXAMPLES A. Manufacture of the mixture of racemates from the compound of Formula III (a) 4-berzzyloxy-fi-methyl-,8-nitrostyrene. 153 gs. (0.720 mol.) of p-benzyloxybenzaldehyde, 72.5 mls. (76.0 gs.=l.01 mol.) of nitro-ethane and 31.5 mls. of n-butyl amine, dissolved in 400 mls. of toluene, were boiled for 18.5 hours while the liberated water was distilled. Then the toluene was distilled at reduced pressure, during which process the above-mentioned product crystallized spontaneously. After washing with petroleum ether, 0.43 mol. of crystalline product was obtained (this is 60%) with melting point from 144 to 146 C.

(h) 2-(4-benzyl0xyphenyl)-1-methyl ethyl amine. A hot solution (35 C.) of 78.5 gs. (0.292 mol.) of 4- benzyloxy-B-methyl-B-nitrostyrene was added, While stirring, to a suspension of 50 gs. of LiAlH in 850 mls. of tetrahydrofurane within a period of A of an hour. Boiling the mixture for another hour was followed by cooling below room temperature, whereupon 70 mls. of water were added under ice cooling. After several hours stay, the deposit was filtered off and washed with tetrahydrofurane. The filtrates and the washing liquid were dried together with Na SO and then evaporated to dryness at reduced pressure. The crystalline residue (59 gs.) was again dissolved in 50 mls. of diethyl ether and this solution extracted with 150 mls. of 2 n HCl. The hydrochloric-acid aqueous layer was subsequently washed with ether and then 35 mls. of 50% NaOH aq. were added. The alkaline solution was extracted with ether, the ethereal solution dried with Na SO and then evaporated to dryness. The crystalline residue weighed 52 gs., this is 74% Eq. weight 244, calculated 241.

(c) N-p-bemyloxyphenyIisopropyl-[3(3,4'-dibenzyloxy plzenyl)-B-oxoethyl amine (Formula IV) .139.4 gs. (0.58 mol.) of 2-(4-benzyloxyphenyl)-1-methyl-ethyl amine were dissolved in 250 mls. of absolute ethanol and this solution had added to it at room temperature 95.5 gs. (0.232 mol.) of finely powdered 3,4-dibenzyloxy-2 brom-acetophenone (Recueil 71 (1952), 933). After shaking for a few minutes, a clear solution was obtained, the temperature rising to about 35 C. The HBr-salt of the initial amine present in excess started crystallizing. After shaking the mixture for another 20 minutes, 1300 mls. of diethyl ether were added. The deposit was sucked off and washed with ether, the washing water added to the filtrate and then 400 cos. of 2 n hydrochloric acid added to this liquid. A crystalline deposit then resulted, which was filtered off and washed successively with 2 ls. of water and 2 ls. of ether. After drying, 83 gs. (0.137 mol.=54%) of the hydrochloric acid salt of the ketone of Formula IV wtih a melting point (with dissociation) from 204 to 210 C. were obtained.

(d) Reduction of the ketone of Formula IV to the mixture of racemates of N-p-benzyloxyphenylisopropyl- ,3-(3',4-dibenzyl0,\yphenyl)-t3-hydroxy-ethyl amine (Formula III).4.40 gs. of NaOH (0.11 mol.) dissolved in 50 mls. of water, and 200 mls. of tetrahydrofurane were added to a solution of 67.0 gs. (0.111 mol.) of the hydrochloride of the tribenzyl ketone, obtained as described sub in 1.7 litres of methanol. Immediately thereafter 13.0 gs. (0.345 mol.) of NaBH in 500 mls. of methanol and 5 mls. of 2 11 NaOH were added to this solution. The mixture was heated to boiling point and then boiled for another 2 hours with reflux cooling. Subsequently 1.5 litres of solvent were removed by evaporation at reduced pressure, whereafter 2 litres of water were added and another 1.6 litres of liquid distilled again at reduced pressure. Now, an oil was separated in the remaining liquid. 500 mls. of benzene were added, in which the oil dissolved. The benzene and the aqueous layer were separated, the benzene phase dried with Na SO and evaporated to dryness in vacuo to form a sticky residue. The residue was dissolved in 150 mls. of diethyl ether while heating. After a short stay at room temperature, the base crystallizes from this solution.

The crystallisate was filtered off, washed with ether and dried. Yield 60 gs. this is 94%. The mixture of racemates had a melting range about from 55 to 75 C. B. Separation of the mixture of racemates oftribenzyl compounds (I) By fractionated crystallization of the free bases. 30 gs. of the racemic mixture of the bases of Formula III obtained as described sub A were dissolved in 150 mls. of

diethyl ether. After storage at room temperature for 16 hours there was a beginning of crystallization. After scratchng and another hours stay, 8.3 gs. of crystallizate with melting point from 65.5 to 72 C. could be separated. After crystallization from a mixture of benzene and petroleum ether, 7 gs. of the tribenzyl-a base with melting point from 69 to 72 C. were obtained therefrom.

The ether filtrate of this first fraction was stored in a refrigerator (0 to 5 C.) for 1 /2 hours, whereafter a second crystallizate of 7.5 gs. with melting range from 83 to 92 C. was sucked off. After crystallization to constant melting point from a mixture of benzene and petroleum ether, 4 gs. of the tribenzyl-[3 base with melting point from 92 to 94 C. could be obtained from this fraction.

Of the two racemates, for example the benzoic-acid salts were obtained in the following manner:

5.7 gs. of base and 1.7 gs. of benzoic acid were dissolved in 250 mls. of ethanol. Then 40 mls. of water were added, whereafter the benzoic-acid salt crystallized spontaneously. After filtration and washing with ethanol and water (5:2), the pure salts were obtained, the OL- benzoate with melting point from 1535 to 154 C. (after crystallization from benzene from 156 to 158 C.), the fi-benzoic with melting point from 138.5 to 139 C.

From these salts, the racemically pure bases were ob tained again in substantially theoretical yield by taking up the salt in water, adding dilute caustic-soda lye, extracting the solution with ether and allowing the base after partial evaporation to dryness to crystallize from the ether. In this proces the a-base showed the remarkable phenomenon that now the modification with a melting point of about 72 C. and now that with a melting point of about 88 C. crystallized.

(II) Separation of the mixture of racemates of tribenzyl by first converting the mixture of free bases into a mixture of salts.61.4 gs. of (0.107 mol.) of a mixture of bases of tribenzyl obtained as described sub A, were taken up in 900 mls. of ethanol, whereafter a solution of 18.5 gs. (0.108 mol.) of p-toluene-sulphonic acid in 100 mls. of water and rnls. of diethyl ether were added.

After 5 days stay at room temperature, 26 gs. of crystallizate with a melting range (dissociation) from 132 to to 137 were filtered off. Half a litre of solvent was removed from the filtrate by evaporation, whereupon after another 4 days stay another 3.5 gs. of crystallizate, melting from 133 to 137 C., were collected. The crystallizates were dissolved together while shaking, in a mixture consisting of 150 mls. of water, 50 mls. of ethanol, 25 mls. of 2 n NaOH and 200 mls. of benzene. The aqueous layer was separated and washed twice with mls. of benzene and once with 100 mls. of ether. The layers of benzene-f-ether were then washed thrice with 100 mls. of water and dried with Na SO followed by evaporation to about 100 mls. After adding mls. of petroleum ether to this residue 21 gs. of substance with melting point from 86 to 95 C. crystallized. After crystallizing twice from a mixture of benzene and petroleum ether, 17.5 gs. of the pure tribenzyl-,6 base with melting point from 94 to 95 C. were obtained therefrom.

50 mls. of 2 11 NaOH, 600 mls. of benzene and 1 litre of water were added to the filtrate of the 29.5 gs. of salt crystallizate. After shaking, the layers were separated. The aqueous layers was washed thrice with 250 mls. of benzene, whereafter the organic liquid layers were added together and washed four times with 500 mls. of water. After drying with Na SO the organic liquid was evaporated at reduced pressure to about mls. After adding mls. of petroleum ether, 32.5 gs. of substance with melting point from 70 to 74 C. crystallized within 15 hours (at room temperature). After crystallization from a mixture of benzene and petroleum ether, 24 gs. of the tribenzyl-a base with melting point from 71 to 72 7 C. could be isolated. Upon heating to C., the molten base resolidified and then melted at to 88 C. The benzoate of the tribenzyl-u base thus obtained melted at 156 to 158 C.

C. Separation of the three benzyl groups from the racemically pure lribenzyl compounds of Formula III for obtaining the racemically pure N-(p-hydroxy-phcnylisopropyDarterenols of Formula I 15 mls. of a 1% solution of PdCl in water, to which 1.5 gs. of norite had been added, and 75 mls. of water were hydrated, sucked off and washedwith water. This pre-hydrated catalyst was then added to a suspension of 9.05 gs. (0.013 mol.) of the ut-tribenzyl benzoate with melting point from 156 to 158 C., obtained as described sub B, in 600 mls. of ethanol. The mixture was then shaken with hydrogen at 1.1 atm. at room temperature. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the filtrate evaporated at reduced pressure to about mls. Subsequently, 50 mls. .of water were added and the liquid was again evaporated at reduced pressure until it became turbid. After 15 hours stay at about 5 C. 4.8 gs. of crystallizate could be filtered oil. This benzoate of the ot-racemate of Formula I crystallised into rosettes. In determining the melting point at a heating rate of 2/min., vitrification was found at 102 to 108 C., liquefaction at to 110 C. and dissociation at to 133 with formation of gas.

1 g. of this tit-benzoate was dissolved in 15 mls. of water while heating, whereafter 1.1 mls. of 2.5 n NH OH- were added at 60 C. 0.64 g. of the free tit-base of Formula I crystallized, which base melted with dissociation at about 171 to 173 C. From this base, for example the phenoxy-acetate with melting point (with dissociation) from 175 to 176 C. and the phenyl acetate with melting point (with dissociation) from 156 to 158 C. could be obtained.

In quite a similar manner the tribenzyl-fi-benzoate was converted into the ,B-benzoate of the base of Formula I which crystallizes into thin plates containing about 11% of crystal water. Upon drying in vacuo over P 0 while 8 2. A member selected from the group consisting of a racemate of the compound N-p-benzyloxyphenylisopropyl-fi-(3,4'-dibenzyloxypheny1) B hydroxyethyl amine with melting point from 92 to 94 C. and pharmacologically acceptable acid addition crystalline. salts thereof.

3. A member selected from the group consisting of a 'racemate .of the compound N-p-benzyloxyphenylisopropyl-fl-(3',4'-dibenzyloxyphenyl) B hydroxyethyl amine with melting point from 70 to 72 C. and pharmacologically acceptable acid addition crystalline salts thereof.

4. A member selected from the group consisting of a racemate of the compound N-p-benzyloxyphenylisopropyl-,8-(3',4'-dibenzyloxyphenyl) 5 hydroxyethyl amine with melting point from 85 to 88 C. and pharmacologically acceptable acid addition crystalline salts thereof.

5. The benzoate of N-p-benzyloxyphenylisopropyl-,8- (3',4'-dibenzyloxyphenyl)-fl hydroxyethyl amine with melting point from 156 to 158 C.

6. The benzoate of N p henzyloxyphenylisopropyl-fi- (3,4'-dibenzyloxyphenyl)-;8 hydroxyethyl amine with melting point from 138 to 139 C.

7. The p-toluene sulphonate of N-p-benzyloxyphenylisopropyl-B-(3',4 dibenzyloxyphenyl) ,6 hydroxyethyl amine with melting point from 137.5 to 138 C.

8. A method of producing the individual racemates of a compound selected from the group consisting of the base and the pharmacologically acceptable acid addition crystalline salts thereof from a mixture of racemates of a member selected from the group consisting of and the pharmacologically acceptable acid addition crystalline salts thereof comprising the steps of isolating a pure racemate from said mixture of racemates by fractional crystallization and then converting said pure racemate into a pure racemate of said compound.

9. A method of producing the mixture of racemates of claim 8 comprising reducing a member selected from the group consisting of a racemic ketone of the formula heating to about 60 C., the crystal water is extracted. The salt thus dried is hydroscopic.

In determining the melting point of this benzoate at a I heating rate of 2/min., vitrification was found at 111 to 112 C., liquefaction at 112 C. and dissociation at C. to 146 C. with evaluation of gas.

and the pharmacologically acceptable acid addition crys- 55 talline salt thereof.

10. The method of claim 8 wherein the conversion is carried out by catalytic hydrogenation.

11. The method of claim 10 wherein a mixture of racemates of the benzoate of is employed.

12. The method of claim 8 wherein the base, the benzoate of which melts at 138 C.-139.5 C. and the 70 base the benzoate of'which melts at 156 C.158 C. are

isolated by zfractional crystallization from a racemic mixture thereof.

13. The method of claim 12 wherein the fractional crystallizationtakes place from ether.

14. The method of claim 8 wherein p-toluene-sul- 9 10 fonic acid is added to a solution of a mixture of the racemates 0f the fcrmula and the p-toluene sulfonate of one of said racemates is 10 FOREIGN PATENTS separated therefrom in crystalline form. 31 420 12 15. The method of claim 14 wherein the crystalliza- 1 i g gfii tion takes place from a. mixture of ethanol and water.

OTHER REFERENCES References Cited by the Examiner 15 Van Dijk et 211.: Recueil des Trav. Chem. des Rags UNITED STATES PATENTS B35, vol. 78, pages 2242 (1959).

3,068,283 12/1962 Kaiser et a1. 260-5705 3,078,307 2/1963 Craig et a1 260 570.8 CHARLES B. PARKER, Primary Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF N-P-BENZYLOXYPHENYLISOPROPYL-B-(3'',4''-DIBENZYLOXYPHENYL)-B-HYDROXYETHYL AMINE AND PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION CRYSTALLINE SALTS THEREOF. 